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101 Theory Drive: A Neuroscientist's Quest for Memoryby Terry McDermott
The Talking Cure
Save for Lynch, Lynch Lab was empty the day I arrived, a clear blue winter morning in the last week of December 2004. Outside, the parking lot contained nothing but clean black asphalt and bright white lines. Inside, the double ranks of stainless-steel lab benches were bare and quiet. Much to Gary Lynch’s chagrin, every single one of the dozen or so scientists, students, and technicians who worked in the lab had gone on holiday. Lynch’s attitude toward other people’s vacations could most charitably be described as dim. He worked 365 days a year. Why couldn’t they? Especially now.
Scientists in Lynch’s lab at the University of California, Irvine, had recently developed a technique that Lynch, a neuroscientist who had been investigating the biochemistry of memory for more than thirty years, thought would allow researchers for the first time to visualize a trace of memory; that is, to see a map of the physical changes in the brain that occur when a memory is made. This was not an insignificant undertaking. For at least a century, scientists had been trying—and failing—to do exactly what Lynch thought his lab was on the verge of accomplishing: to teach an animal a new skill or experience; to, in other words, expose that animal’s brain to something in the exterior world, then look deeply enough into the close, dark, complicated space that is the mammalian brain and say, with certainty, “There! Right there! That’s it.” “The thing itself,” Lynch sometimes called it, making it sound like a rumored but never- quite-glimpsed spirit in the night.
Such a physical trace of memory is commonly called an engram. Karl Lashley, a famed American psychologist, had popularized the term in the mid-twentieth century and had devoted a significant portion of his career to pursuing it. His search had been exhaustive and, in the end, fruitless.
“This series of experiments has yielded a good bit of information about what and where the memory trace is not,” Lashley wrote. “It has discovered nothing directly of the real nature of the engram. I sometimes feel, in reviewing the evidence on the localization of the memory trace, that the necessary conclusion is that learning just is not possible. It is difficult to conceive of a mechanism that can satisfy the conditions set for it. Nevertheless, in spite of such evidence against it, learning sometimes does occur.”
The history of memory research since Lashley had been rife with heated disagreements about whether such a thing as an engram actually existed, about whether such a thing could actually be seen, about what such a thing would look like if it did exist and could be seen, about where it would be, and, especially, about what did or did not occur inside the brain cells, called neurons, that would cause such a thing to exist. If, that is, it did.
Of course, Lashley’s original impulse had been right. It had to be. If memory left no mark, then there could be no such thing as memory, no such thing as a personal past, no learning, no store of intimate and exotic knowledge. And if not that, then how to explain your sudden blinding reminiscence of that day in seventh grade when you dove headlong for the loose ball and crashed nose first into the bleachers and the pain was so sharp and bright you thought you had broken your brain, or the dense, long evening in the summer of the next year when you kissed Sharon Connelly, and she kissed back? If these things had truly happened, if you knew them to be true and had kept each in its own special place all that while, there was memory and it had only to be excavated from wherever it lay. Where was that place? What did it look like? Half a century after Lashley, no one knew.
Many of the experimental data marshaled from contemporary investigations of memory have been frail and indirect, some so slight that within the intimate, intensely competitive, and feud-ridden field of memory research, they are sarcastically dismissed as “investigator dependent,” meaning they are derived from experiments done in particular labs but that no one outside those labs could replicate and few believed. Even the best of the data—that is, that which came from experiments that can be reliably duplicated—is often so narrowly focused as to be nearly useless in building larger explanations of how memories might be laid down.
The experiments—the good and bad alike—used to generate all these results are, even when they work, seldom designed to test questions directly. They can’t be. This is more than anything a reflection of the fundamental difficulty of neuroscience. Lashley failed not because he was wrong, but because he had no good way to look for his answer. The secrets are buried too deeply to be uncovered through direct observation. They literally can’t be seen. The scale of the target environment—the brain—is forbidding. The three and one-half pounds of the average human brain are thought to contain something on the order of 100 billion neurons. The average neuron is far smaller than the thickness of a human hair, yet it contains many thousands of proteins, acting sometimes in unison, often in opposition, almost always in complicated combinations.
Almost all memory research—in Lashley’s day as now—is done by implication. For most of human history, memory investigators have been forced to stand outside the brain, trying to determine what goes on in the lost world inside. The tools long did not exist to look directly for the answers to researchers’ questions. Lynch was part of the generation of scientists that came after Lashley and for the first time moved the search into the complex machinery of the brain’s interior. His generation has advanced to the threshold of addressing some of the great fundamental questions of the human condition. The move from outside in has finally given them a fighting chance to uncover the molecular mechanisms of the brain—to learn what actually happens when people think and talk, how they learn and remember.
That first day, my conversation with Lynch went something like this:
ME: I’m interested in spending time in a laboratory, like yours, where the principal focus is the study of memory. I’d like to explain how memory functions and fails, and why, and use the work in the lab as a means to illustrate how we know what we know.
LYNCH: You’d be welcome to come here. This would actually be a propitious time to be in the lab.
ME: Why’s that?
LYNCH: Because we’re about to nail this mother****er to the door.
In the years after that meeting, I spent a great deal of time in Lynch’s lab. I spoke with the other scientists and students who worked there and observed their experiments; I read papers they and others published; and I learned how to perform some of the most rudimentary tasks of their basic experiments. But what I mostly did at Lynch Lab was talk to Lynch. Or, rather, I listened as Lynch expounded on mammalian biology and brain science. This was a generous undertaking on his part, as I had arrived at the lab largely ignorant of the field. Listening to him often entailed following swooping, exhilarating flights over time and intellectual terrain. Bear with me, he sometimes said, this might not seem connected to what we’ve been talking about, but it will circle back. Ten, twenty, or thirty minutes later—often after side trips to Planck’s constant, or Yankee Stadium, or Bismarck’s Germany, or his childhood backyard in Delaware—it did.
Lynch almost always spoke in such a way that his huge ambition, self- regard, and lack of pretense were vividly displayed. He was unreserved, witty, juvenile, insightful, and learned in ways that were surprising. His conversation rippled with allusion. He was more apt to quote Cormac McCarthy than Charles Darwin. That first claim, that he was “about to nail this motherfucker to the door,” was, in addition to being a status report on his research, a reference to Martin Luther (like Lynch, a conspirator against the establishment) nailing his indictment of the Roman Catholic Church to a cathedral door in sixteenth-century Germany. In subsequent talks, Lynch made similar on-the-fly references to, among many other things, left- handed relief pitchers, Moses, British naval history, the venture capital market, Kaiser Wilhelm II, Maxwell’s equations, the ur-city of Ur, Dylan, Kant, Chomsky, Bush, Tacitus (whom he compared, unfavorably, to Suetonius), Titian, field theory, drag racing, his father’s perpetual habit of calling him (intentionally) by the wrong name, his career as a gas jockey at an all-night service station, Pickett’s charge at Gettysburg, Caesar’s crossing of the Rubicon, and the search for the historical Jesus.
He was no less prolix in more formal settings. Eniko Kramar, a senior scientist in Lynch’s lab, recounted a talk he had given to a conference on schizophrenia. Lynch outlined an emerging hypothesis based mainly on novel experiments then being conducted in the lab, but his talk ranged all the way back to his graduate school studies at Princeton. He even showed a slide, without identifying its origin, from his 1968 dissertation. Besides the fact that work he had done thirty-five years earlier was still relevant, Kramar said, “the sweep and elegance of it was breathtaking.”
Lynch had moved his lab and office numerous times during his Irvine career, often as the result of some perceived, or real, slight. For a while his office was just a desk at the end of a communal hallway. The current lab was at 101 Theory Drive, in a tilt-up office park between a toll road and the University of California, Irvine, main campus. Lynch had ended up in the office park largely because everyone, including him, had concluded that all parties would be better served if there were some physical distance between Lynch and his university peers.
The university had put up the low-rise buildings in the 1990s in partnership with a developer, intending them to become a research nexus where academic and entrepreneurial talent could mix. It hadn’t quite worked out that way. The rents were so high few truly innovative companies could afford the space. Most of the tenants had little if anything to do with the university. En route to the office park’s resident Starbucks, Lynch often trailed whole convoys of shirttailed, triple-shot-latte addicts who spent their days and nights writing World of Warcraft code. That their dense, imaginary world was next door to a lab of neurophysiologists cutting up rat brains was utterly unknown to them. None of the work in the lab was apparent from the outside. The beige-on-beige, spray-on stucco building was indistinguishable from those in front of, beside, and behind it. More than once I walked into the wrong lobby.
The lab’s address on Theory Drive was a developer’s idea of a scientific street name. (The next left down the main road is Innovation Drive.) Lynch finds the name embarrassing. A kind of lunch- bucket anti-intellectualism prevails in academic biology, and Lynch was sometimes seen as guilty of its gravest sin—ambition. He mocks the criticism: “ ‘Oh a theory, another theory. That’s cute. Look, guys, Gary has another theory.’ ” For all his bombast and the resentments it provoked, Lynch was not eager to antagonize his many enemies heedlessly. He was respectful of the intellectual protocols that placed formal biological theory on a very high shelf he had yet to reach.
It is a mark of the difficulty of the life sciences—biology and its many complicated derivatives—that to call something a theory is not to slight but to honor it. Theory, the developmental biologist P. Z. Myers has written, is what biologists aspire to. Scattered across the globe, more than a dozen places proudly proclaim themselves home to the pursuit of theoretical physics. But as Lynch notes, it is no accident that there is “no Institute for Neuroscience Theory.” His protestations aside, he was almost constantly struggling for higher explanations, to make things cohere, to fit data into what the analytical philosopher Willard V. O. Quine called the web of science. In any event, insofar as the street was concerned, Lynch said, “I would have called it Hypothesis Drive.”
Hypotheses and theories, while related, are more different than alike. The hypothesis is the fundamental organizing principle in scientific research. Its “if this, then that” structure underlies almost all scientific investigation. If is the key word in that construction. An hypothesis is a set of questions. A theory is a set of proposed answers.
Imagine the brain as a huge storehouse with shelf after shelf, miles long, filled with a wild assortment of tableware—teacups, saucers, platters, ceramic bowls, crude pottery, fine china, simple dinner plates. The tableware may once have been stored tidily, but an earthquake has leveled the interior. The resulting huge pile of wrecked shelves and broken plates is the geography that a neuroscientist must navigate while trying to discern patterns and coherence in the brain.
An hypothesis is what someone, after surveying the wreckage of that pile of plates, might offer to begin putting the pieces back together. If all the blue pieces go together, then maybe we can rebuild the bowls. Frequently—always, really—the view of the pile inside the brain is incomplete. Pieces big and small are missing. Sometimes they sit out of sight for decades, even centuries, with no one willing or able to imagine their having a place in the reconstructed order. Perhaps they’re obscured by other pieces, or in another room, or lying in plain sight but are the wrong color. Who could possibly have imagined that brown shard would fit between the two blue? Lynch’s true gift is an ability to see how varied pieces might fit together, to intuit that somewhere in the room—under that blue-black pile, perhaps—there ought to be a piece of green ceramic.
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